Machado-Joseph Disease

BEIJING, China I March 24, 2025 I SineuGene Therapeutics Co., Ltd. (“SineuGene”), a clinical-stage biotech company pioneering innovative therapies for neurological disorders, today announced that the U.S. Food and Drug Administration (FDA) has cleared its Investigational New Drug (IND) application for SNUG01 — a first-in-class TRIM72 (Tripartite Motif Protein 72)-targeted gene therapy candidate for amyotrophic lateral sclerosis (ALS). The clearance authorizes a global Phase I/IIa clinical trial designed to evaluate SNUG01’s safety, tolerability, and preliminary efficacy in adults with ALS through a dose-escalation and expansion study. ALS is a rapidly progressive neurodegenerative disorder marked by motor neuron degeneration in the brain and spinal cord, leading to muscle weakness, atrophy, and eventually respiratory failure. Median survival time post-diagnosis is 3–5 years. Despite being the most prevalent adult-onset motor neuron disease, existing therapies offer limited clinical benefits, slowing progression only marginally and leaving no curative options for patients. SNUG01 leverages groundbreaking research carried out by Dr. Yichang Jia’s laboratory at Tsinghua University, whose team identified TRIM72 as a multifunctional neuroprotectant. The therapy utilizes a recombinant adeno-associated virus serotype 9 (rAAV9) capsid to deliver the human TRIM72 gene via intrathecal administration. Preclinical studies demonstrate TRIM72’s ability to counteract ALS pathogenesis through several synergistic mechanisms such as reducing oxidative stress by scavenging reactive oxygen species (ROS), restoring mitochondrial homeostasis, suppressing stress granule dysregulation, inhibiting neuroinflammatory cascades, and enhancing neuronal membrane repair capacity In an investigator-initiated trial (IIT) at Peking University Third Hospital, SNUG01 demonstrated a favorable safety and tolerability profile, along with early efficacy signals in both functional clinical assessments and key biomarkers of neurodegeneration. These results enhance the translational validation of TRIM72, bridging target discovery, preclinical models, and human proof-of-concept. Unlike mutation-targeting gene therapies, SNUG01 leverages multiple neuroprotective mechanisms, offering a critical advantage for over 90% of ALS patients with sporadic (non-familial) disease. This unique multi-target approach positions SNUG01 as a first-in-class candidate for the majority of ALS cases, addressing an urgent unmet need in this underserved population. SineuGene will partner with a leading global consortium of academic and clinical institutions to conduct a multi-regional clinical trial, expediting validation of SNUG01’s safety and therapeutic efficacy profile across a diverse ALS patient populations. About SineuGene SineuGene Therapeutics Co., Ltd., often referred to as “SineuGene,” is a biotechnology company focused on developing innovative therapies for neurological diseases. Established in late 2021, the company builds on over a decade of scientific research conducted by Dr. Yichang Jia’s team from School of Medicine, Tsinghua University. SineuGene uses advanced technologies such as adeno-associated virus (AAV) vector-mediated gene delivery and editing and antisense oligonucleotide (ASO)- based gene expression regulation. The company has created a diverse pipeline that targets major neurological diseases, including Amyotrophic Lateral Sclerosis (ALS), stroke, Parkinson’s disease, Alzheimer’s disease, Spinocerebellar Ataxia type 3, and Huntington’s disease. SineuGene is dedicated to transforming groundbreaking research into effective treatments, aiming to meet the unmet medical needs in the field of neurology. Website: www.sineugene.com SOURCE: SineuGene Therapeutics

引言 在人类基因组的浩瀚密码中,一段名为"Huntingtin(HTT)"的基因序列暗藏杀机。当这个基因上出现过多CAG三核苷酸重复时,就会引发被称为"亨廷顿舞蹈症(Huntington's disease,HD)"的神经退行性疾病。患者从肢体不受控制地舞动开始,逐渐丧失运动能力、认知功能,最终走向生命的终点。2月11日Cell的研究报道“Distinct mismatch-repair complex genes set neuronal CAG-repeat expansion rate to drive selective pathogenesis in HD mice”，揭开了惊人发现：原本担任基因"校对员"的错配修复基因，竟在这场神经死亡风暴中扮演关键角色。 基因纠错系统叛变：从守护者到加害者 (Mismatch Repair, MMR)我们的细胞自带精密的基因纠错系统——错配修复机制(MMR)。就像印刷厂的质检员,MSH3、PMS1等基因组成的分子机器(MutSb-MutLb复合体)原本负责检测并修复DNA复制错误。但在HD患者中,这套系统出现了匪夷所思的"叛变":它们持续推动CAG重复序列的体细胞扩增,使得神经元中的CAG重复数从遗传的140次飙升至260次。 小鼠实验显示,纹状体中型多棘神经元(Medium Spiny Neurons, MSNs)中的CAG每月以8.8次的速度线性扩增。当敲除MSH3基因后,这个速度直接降至2.3次;若是彻底删除该基因,扩增完全停止。这解释了为何携带140次CAG重复的HD模型小鼠(Q140)在12月龄时会出现特征性的突变蛋白聚集,而基因改造小鼠却能保持神经健康。临界点效应：150次重复改写细胞命运 (CAG repeat threshold)研究团队通过单神经元CAG测序发现惊人规律:当MSN神经元中的CAG重复超过150次(threshold),就会触发突变的亨廷顿蛋白(mHTT)的核内聚集。这个临界点犹如打开潘多拉魔盒的钥匙,引发以下连锁反应: 转录组崩溃:涉及8,900多个基因的表达紊乱,包括突触功能相关基因下调30% 染色质解构:开放式染色质区域异常增加22%,影响PRC2复合体介导的表观调控 星形胶质细胞活化:纹状体区域GFAP阳性细胞数量增加2.5倍时空双维打击：从纹状体到皮层的病变演进 (Spatiotemporal pathogenesis)疾病进展展现精确的时空规律:运动调控中枢纹状体最早在6月龄出现病理改变,而认知相关的皮层病变要到12月龄才显现。这种差异与皮层神经元的CAG扩增速率(每月4.2次)显著慢于纹状体(每月8.8次)直接相关。更惊人的是,在疾病晚期的20月龄小鼠中,去除MSH3基因仍能清除90%的蛋白聚集体,逆转星形胶质细胞增生。曙光初现：基因编辑改写治疗范式 (Therapeutic implications)该研究为HD治疗指明三个突破方向: 精准靶向：针对MutSb-MutLb复合体的特异性抑制剂开发,相比广谱DNA修复调控更具安全性 动态监测：通过PET检测mHTT聚集体或脑脊液中的CX3CL1等生物标志物,建立150次重复的早期预警系统 时序干预：在青少年期进行基因治疗,阻止CAG扩增突破临界点 动物实验证实,MSH3基因敲除不仅逆转病理改变,更显著改善运动障碍:在测试中,治疗组小鼠的运动持续时间延长4倍,步态失调指数下降76%。这为即将进入临床试验的反义寡核苷酸(ASO)疗法提供了关键理论支撑。治疗新纪元：亨廷顿的基因密码 (Beyond Huntington's)这项突破性发现的影响已超越单一疾病范畴。在超过40种由三核苷酸重复扩展引发的神经退行性疾病中,如脊髓小脑共济失调3型(SCA3)和肌萎缩侧索硬化症(ALS),类似的DNA修复机制异常可能普遍存在。研究团队建立的"体细胞扩增动力学模型",为这类疾病提供了全新的共性治疗策略——通过调控特定修复基因的表达节奏,在细胞命运失控前重启生命密码的正确解读。 当我们凝视显微镜下那些因基因重复而扭曲的神经元,看到的不再是绝望的终点,而是科学利剑劈开的希望之路。从精准编辑致病基因到动态监测扩增进程,这场对抗神经退化的战役,正在改写现代医学的剧本。 参考文献 https://www.cell.com/cell/fulltext/S0092-8674(25)00100-X 责编|探索君 排版|探索君 转载请注明来源于【生物探索】 声明：本文仅用于分享，不代表平台立场，如涉及版权等问题，请尽快联系我们，我们第一时间更正，谢谢！ End 往期精选 围观 Science | T细胞为何会“疲惫不堪”？代谢与表观遗传的答案 热文 Nature Biotechnology | 免疫治疗新突破：如何精准锁定病变细胞？ 热文 Cell | 突破传统认知：电突触如何动态调控神经网络行为 热文 Nature Biotechnology | 如何解码非编码区的“基因组暗物质”？ 热文 Nature Methods | 如何利用温度精准操控细胞？细胞命运调控的新思路

PASADENA, Calif.--( BUSINESS WIRE )--Arrowhead Pharmaceuticals, Inc. (NASDAQ: ARWR) today announced that the global licensing and collaboration agreement with Sarepta Therapeutics (NASDAQ: SRPT) announced on November 26, 2024, has now closed. Closing of the transaction was subject to the expiration or termination of the waiting period under the Hart-Scott-Rodino Antitrust Improvements Act of 1976 and other customary conditions. Summary Financial Terms Upon closing, Arrowhead receives a $500 million upfront payment and $325 million through the purchase by Sarepta of Arrowhead common stock priced at $27.25 per share. Arrowhead will also receive $250 million to be paid in annual installments of $50 million over 5 years. Arrowhead also has the potential to receive $300 million in near-term payments associated with the continued enrollment of certain cohorts of a Phase 1/2 study of ARO-DM1, which Arrowhead is on track to achieve during the next 12 months. Arrowhead is eligible to receive development milestone payments of between $110 million and $410 million per program and sales milestone payments of between $500 million and $700 million per program. Arrowhead is also eligible to receive tiered royalties on commercial sales up to the low double digits. Summary of Programs under License and Collaboration Agreement Clinical Stage ARO-DUX4, which is designed to target the gene that encodes the DUX4 protein as a potential treatment for patients with facioscapulohumeral muscular dystrophy type 1, currently dosing patients in a Phase 1/2 clinical study. ARO-DM1, which is designed to reduce expression of the dystrophia myotonica protein kinase (DMPK) gene in skeletal muscle as a potential treatment for patients with type 1 myotonic dystrophy, currently dosing patients in a Phase 1/2 clinical study. ARO-MMP7, which is designed to reduce expression of matrix metalloproteinase 7 (MMP7) in the lung as a potential treatment for idiopathic pulmonary fibrosis, currently dosing patients in a Phase 1/2 clinical study. ARO-ATXN2, which is designed to silence expression of the toxic ATXN2 protein in the CNS as a potential treatment for spinocerebellar ataxia 2 (SCA2), currently in a Phase 1/2 study that is open for enrollment. Preclinical Stage ARO-HTT for patients Huntington’s disease expected to be CTA-ready in 2025 ARO-ATXN1 for patients with spinocerebellar ataxia 1 (SCA1) expected to be CTA-ready in 2026 ARO-ATXN3 for patients with spinocerebellar ataxia 3 (SCA3) expected to be CTA-ready in 2026 Discovery During the five-year term, Sarepta can propose up to six new CNS or muscle targets for which Arrowhead will perform discovery and preclinical development. Sarepta would then receive an exclusive license to those programs and be responsible for clinical development and commercialization. Drug Manufacturing Under the agreement, Arrowhead will manufacture clinical drug supply for all programs arising out of the license and collaboration, and commercial drug product for the four programs currently in clinical trials. About Arrowhead Pharmaceuticals Arrowhead Pharmaceuticals develops medicines that treat intractable diseases by silencing the genes that cause them. Using a broad portfolio of RNA chemistries and efficient modes of delivery, Arrowhead therapies trigger the RNA interference mechanism to induce rapid, deep, and durable knockdown of target genes. RNA interference, or RNAi, is a mechanism present in living cells that inhibits the expression of a specific gene, thereby affecting the production of a specific protein. Arrowhead’s RNAi-based therapeutics leverage this natural pathway of gene silencing. 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Without limiting the generality of the foregoing, words such as “may,” “will,” “expect,” “believe,” “anticipate,” “hope,” “intend,” “plan,” “project,” “could,” “estimate,” “continue,” “target,” “forecast” or “continue” or the negative of these words or other variations thereof or comparable terminology are intended to identify such forward-looking statements. In addition, any statements that refer to projections of our future financial performance, trends in our business, expectations for our product pipeline or product candidates, including anticipated regulatory submissions and clinical program results, prospects or benefits of our collaborations with other companies, or other characterizations of future events or circumstances are forward-looking statements. These forward-looking statements include, but are not limited to, statements about the initiation, timing, progress and results of our preclinical studies and clinical trials, and our research and development programs; our expectations regarding the potential benefits of the partnership, licensing and/or collaboration arrangements and other strategic arrangements and transactions we have entered into or may enter into in the future; our beliefs and expectations regarding milestone, royalty or other payments that could be due to or from third parties under existing agreements; and our estimates regarding future revenues, research and development expenses, capital requirements and payments to third parties. These statements are based upon our current expectations and speak only as of the date hereof. Our actual results may differ materially and adversely from those expressed in any forward-looking statements as a result of numerous factors and uncertainties, including the impact of the ongoing COVID-19 pandemic on our business, the safety and efficacy of our product candidates, decisions of regulatory authorities and the timing thereof, the duration and impact of regulatory delays in our clinical programs, our ability to finance our operations, the likelihood and timing of the receipt of future milestone and licensing fees, the future success of our scientific studies, our ability to successfully develop and commercialize drug candidates, the timing for starting and completing clinical trials, rapid technological change in our markets, the enforcement of our intellectual property rights, and the other risks and uncertainties described in our most recent Annual Report on Form 10-K, subsequent Quarterly Reports on Form 10-Q and other documents filed with the Securities and Exchange Commission from time to time. We assume no obligation to update or revise forward-looking statements to reflect new events or circumstances. Source: Arrowhead Pharmaceuticals, Inc.